The orexin peptides (orexin A and orexin B, OxA and OxB), also known as hypocretins, were discovered in 1998 by two groups (Sakurai et al., Cell, 1998, 92, 573 and De Lecea et al., Proc. Nat. Acad. Sci., 1998, 95, 322). These neuropeptides are both derived from the common precursor pre-pro-orexin and are produced in the lateral hypothalamus. OxA is a 33 amino acid residue which has similar potency at both the Ox1R (orexin 1 receptors) and Ox2R (orexin 2 receptors) whereas OxB is made up of 28 amino acids and binds selectively to the Ox2R.
Orexin receptors are believed to be implicated in both feeding behaviour (Sakurai et al., Cell, 1998, 92, 573) and also in regulating sleep architecture (Chemelli et al., Cell, 1999, 98, 437). More recently, it has been shown that orexin receptors are implicated in arousal, reward, learning and memory (Harris et al., Trends Neurosci., 2006, 29, 571).
WO 2003/099276 describes a broad class of compounds, including certain amides, which are useful as factor Xa inhibitors for treating thromboembolic disorders.
We have now discovered a class of compounds that are orexin receptor antagonists. Furthermore, certain compounds of the invention show selectivity for the orexin 1 receptor over the orexin 2 receptor.